In recent years, the use of polymerizable oligomers to form polymeric matrices in situ for a wide variety of applications has greatly expanded. These reagents are generally polymeric materials that are capable of participating in additional polymerization reactions to form polymeric matrices. The use of reactive oligomers of this type to form polymeric matrices provides many advantages over standard matrix-forming technologies including polymerizations utilizing monomers. These oligomeric reagents, or macromers, can be polymerized rapidly, in an aqueous environment if desirable, to form polymeric matrices in the presence of living tissue and cells. The formation of polymeric matrices utilizing macromers of this type provide advantages such as reduced cytotoxicity, control over timing of matrix formation, speed of matrix formation, control over matrix characteristics, and the like. These reagents have found use in many applications, particularly in applications involving the formation of polymeric matrices in the presence of tissue or cells. These applications include the prevention of surgical adhesions, cell encapsulation, controlled drug delivery, tissue coatings, tissue adhesives, and the like.
For the prevention of surgical adhesions, a solution of polymerizable macromers is applied to a site of damaged tissue in a patient. Tissue damage generally occurs as the result of an invasive surgical procedure. During the course of the wound healing process, tissue “adhesions” can form between the damaged tissue and adjacent healthy tissue. The macromer solution is subsequently polymerized forming a solid polymeric matrix after application to the damaged and diseased tissue surface. This matrix acts as a barrier between healing tissue and surrounding tissues thereby preventing the formation of adhesions. If bioresorbable materials are used to form the matrix, the barrier will eventually disappear.
Cell encapsulation methods are generally aimed at surrounding a cell or group of cells with a synthetic material that provides protection from the processes of host immune rejection after the encapsulated cells have been transplanted into an individual. The synthetic material around the cells ideally allows the cells to remain viable and to function properly in order to provide therapeutic value to the host. In order to perform this function, the synthetic material that encapsulates the cells should be resistant to biodegradation and should be sufficiently permeable to allow for diffusion of cellular waste products, nutrients, and molecules involved in cellular responses. Preferably this synthetic material is not permeable to certain host molecules, such as immunoglobulins and complement factors that could contribute to the destruction of the foreign cells.
Advances in cell encapsulation technologies have been focused on improving the permeability, mechanical properties, immune protectivity, and biocompatibility of the encapsulating synthetic material. Various micro- and macro-encapsulation techniques, including microencapsulation by polyelectrolyte complexation, thermoreversible gelation, interfacial precipitation, interfacial polymerization, and flat sheet and hollow fiber-based macroencapsulation have been studied and are reviewed by Uludag et al. (Adv. Drug Deliv. Rev.; 42:29-64 (2000)).
One promising cell encapsulation process, interfacial polymerization, involves the formation of a layer of polymerized material, such as synthetic or natural polymerizable materials, on the surface of a biological substrate. Interfacial polymerization reagents and methods have been described in U.S. Pat. Nos. 5,410,016, and 5,529,914, and Applicant's U.S. Pat. Nos. 6,007,833 and 6,451,622, herein incorporated by reference in their entirety.
For controlled drug delivery, biologically active substances are delivered to desired tissue sites by incorporation into matrix-forming formulations. Tissue surfaces are coated with solutions of polymerizable macromers mixed with one or more biologically active substances and subsequently solidified by polymerization. Using this method, biologically active substances can be delivered to tissues over an extended period of time.
For tissue coatings, macromer solutions are applied to the surfaces of tissue and solidified in situ. The resulting polymeric matrices are useful for tissue healing, restenosis prevention, and the like.
For tissue adhesives, matrices formed by macromer polymerization can be used to adhere tissue surfaces in the body.
For all of these applications, the polymeric matrices themselves, the precursor macromer reagents, and the methods used to initiate and propagate polymerization should be biocompatible and have minimal cytotoxicity. In order to meet these requirements, rapid matrix formation is essential. To achieve rapid matrix formation, polymerization initiation and propagation efficiencies must be maximized. There are several methods of enhancing these efficiencies. One method is to provide the initiator in a polymeric form. Polymeric initiators enhance the initiation efficiency of polymerization reactions. Another method is to include a polymerization accelerator in the polymerization formulation.
Polymerization accelerators are low molecular weight monomers that enhance matrix formation when added to macromer formulations. Unfortunately, the inclusion of these accelerators may have a detrimental effect on the biocompatibility of the polymeric matrix.
The polymerization accelerators of the current invention address these fundamental problems associated with the formation of polymeric matrices in the presence of tissue. The inclusion of these new accelerators into macromer solutions enables the formation of biocompatible matrices when these formulations are polymerized into tissue-contacting matrices.